CD8+PD-1-ILT2+ T Cells Are an Intratumoral Cytotoxic Population Selectively Inhibited by the Immune-Checkpoint HLA-G
CD8+PD-1-ILT2+ T Cells Are an Intratumoral Cytotoxic Population Selectively Inhibited by the Immune-Checkpoint HLA-G
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DOI：
10.1158/2326-6066.cir-18-0764
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发表时间：
2019-10-01
影响因子：
10.1
通讯作者：
LeMaoult, Joel
中科院分区：
文献类型：
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作者：
Dumont, Clement;Jacquier, Alix;LeMaoult, Joel
只有部分癌症患者对临床上使用的免疫检查点抑制剂有反应，并寻求其他治疗靶点。在这里，我们研究了肾透明细胞癌(CcRCC)患者的人类白细胞抗原-G/ILT2检查点，重点研究了表达人类白细胞抗原-G受体ILT2的肿瘤浸润性CD8(+)T淋巴细胞(TIL)。利用转录和流式细胞术，我们鉴定了癌症患者外周血和肿瘤浸润性CD8(+)ILT2(+)T细胞是晚期分化的CD27(-)CD28(-)CD57(+)细胞毒效应细胞。我们观察到CD8(+)、ILT2(+)和CD8(+)、PD-1(+)TIL亚群之间存在明显的二分法。这些亚群有时在TIL群体中以类似的频率存在，几乎不与表型重叠，并通过包括检查点分子和激活和抑制受体在内的独占表面分子集的表达来区分。CD8(+)ILT2(+)TIL具有较成熟的表型和较高的细胞毒分子表达。在外周血T细胞和TIL的体外功能实验中，CD8(+)ILT2(+)T细胞表现出明显高于ILT2-(外周血单核细胞)和PD-1(+)(TILs)T细胞的细胞毒作用和IFNG产生。靶细胞表达的HL A-G特异性地抑制CD8(+)ILT2(+)T细胞的杀伤活性，但不能抑制CD8(+)ILT2(-)(PBMC)或CD8(+)PD-1(+)(TIL)T细胞的杀伤作用，这种作用可通过阻断HLA-G/ILT2的相互作用而被抵消。因此，CD8(+)ILT2(+)TIL可能构成肿瘤微环境中完全分化的细胞毒性T细胞的未开发储存库，独立于免疫疗法靶向的PD1(+)TIL，并被HLA-G特异性抑制。这些结果强调了在抗PD-1/PD-L1的同时或在抗PD-1/PD-L1无应答的情况下，针对HLA-G(+)肿瘤的治疗靶点的可能性。
Only some cancer patients respond to the immune-checkpoint inhibitors being used in the clinic, and other therapeutic targets are sought. Here, we investigated the HLA-G/ILT2 checkpoint in clear-cell renal-cell carcinoma (ccRCC) patients and focused on tumor-infiltrating CD8(+) T lymphocytes (TIL) expressing the HLA-G receptor ILT2. Using transcriptomics and flow cytometry, we characterized both peripheral blood and tumor-infiltrating CD8(+)ILT2(+) T cells from cancer patients as late-differentiated CD27(-)CD28(-)CD57(+) cytotoxic effectors. We observed a clear dichotomy between CD8(+)ILT2(+) and CD8(+)PD-1(+) TIL subsets. These subsets, which were sometimes present at comparable frequencies in TIL populations, barely overlapped phenotypically and were distinguished by expression of exclusive sets of surface molecules that included checkpoint molecules and activating and inhibitory receptors. CD8(+)ILT2(+) TILs displayed a more mature phenotype and higher expression of cytotoxic molecules. In ex vivo functional experiments with both peripheral blood T cells and TILs, CD8(+) ILT2(+) T cells displayed significantly higher cytotoxicity and IFNg production than their ILT2-(peripheral blood mononuclear cells, PBMC) and PD-1(+) (TILs) counterparts. HLA-G expression by target cells specifically inhibited CD8(+) ILT2(+) T-cell cytotoxicity, but not that of their CD8(+) ILT2(-) (PBMC) or CD8(+)PD-1(+) (TIL) counterparts, an effect counter-acted by blocking the HLA-G/ILT2 interaction. CD8(+)ILT2(+) TILs may therefore constitute an untapped reservoir of fully differentiated cytotoxic T cells within the tumor microenvironment, independent of the PD1(+) TILs targeted by immune therapies, and specifically inhibited by HLA-G. These results emphasize the potential of therapeutically targeting theHLA-G/ILT2 checkpoint in HLA-G(+) tumors, either concomitantly with anti-PD-1/PD-L1 or in cases of nonresponsiveness to anti-PD-1/PD-L1.